N-alkyldiethanolamine hydrofluorides and oral hygiene compositions containing them

ABSTRACT

Amine hydrofluorides of the general formula (I): 
     
       
         R—N(CH 2 CH 2 OH) 2 .HF   (I)  
       
     
     In which R is a straight-chain hydrocarbon residue having 10 to 20 carbon atoms exhibit antibacterial and caries-prophylactic activity and can be prepared in high purity. The amine hydrofluorides of the formula (I) can be formulated, optionally in combination with tin fluoride, into oral hygiene compositions such as toothpastes, mouthwashes or chewable tablets.

The present invention relates to amine hydrofluorides and mixtures ofthese amine hydrofluorides, and to a process for the preparation ofthese amine hydrofluorides and their use in oral hygiene compositions.

It is known that oral hygiene compositions, by their cleaning action,make a contribution to the hygiene of the oral cavity and thus to thepreservation of the health of teeth and gums. The cleaning action ofthese oral hygiene compositions is customarily supplemented by admixtureof active compounds which prevent or control pathological symptoms inthe oral cavity, in particular also the formation of bacterial films onthe teeth (plaque). These films consist of polysaccharides, primarily ofdextrans. In addition to the low-molecular weight sugars, thesepolysaccharides form a source of nutrition for the plaque bacteria(mainly streptococci and lactobacillaceae). The plaque bacteriagradually break down the polysaccharides to form acidic degradationproducts (e.g. pyruvic acid, lactic acid etc.). The pH decreaseresulting therefrom brings about the degradation of the tooth enamelknown as caries.

It has therefore already been attempted to take steps against theformation of pathological symptoms in the oral cavity using various oralhygiene compositions comprising antibacterially active substances (e.g.toothpastes, rinsing solutions or dental gels). Active compounds alreadyknown from the prior art are N-octadeca-9-enylamine hydrofluoride(international non-proprietary name “dectaflur”) and in particularN′-octadecyl-N′,N,N-tris(2-hydroxyethyl)-1,3-propanediaminedihydrofluoride (international non-proprietary name “olaflur”). On oraluse of the hygiene composition, these active compounds form a thinhydrophobic film on the tooth enamel, the amine hydrofluoride groupscoming into contact with the tooth enamel. Thus on the one hand thetooth enamel becomes more resistant to acid attacks on account of theCaF₂ covering layer formed, on the other hand the long-chain hydrocarbonresidues form a hydrophobic layer which prevents the formation ofdeposits and the attack of the acidic degradation products on the toothenamel.

The synthesis of olaflur starts from bovine tallow, a fat having a highstearic acid content. The ester groups are hydrolysed, the free fattyacids are converted into the corresponding amides using ammonia andthese are dehydrated to the nitrites. Catalytic reduction thereof yieldsa mixture of primary fatty amines with the main constituentoctadecylamine. Reaction with acrylonitrile and catalytic re-reductionaffords N-octadecyl-1,3-propanediamine, which is hydroxyethylated usingethylene oxide. Amounts of by-products are formed here, as the aminogroups are in some cases under- or over-substituted. The hydroxyethylgroups introduced can also be etherified by means of further ethyleneoxide. The subsequent double hydrofluoridation yields the final productolaflur in technical purity, in whichN′-octadecyl-N′,N,N-tris(2-hydroxyethyl)-1,3-propanediaminedihydrofluoride occurs as the main component. The purification of theby-products is dispensed with for cost reasons.

The presence of these by-products was until now not considered to beinconvenient, since in relation to the film formation on the enamel theyare of secondary importance. However, it has to be taken into accountthat in the course of the global tightening of the official approvalprocedures for pharmaceutical active compounds in future the marketingauthorizations for contaminated active compounds will be more difficultto obtain.

The present invention is based on the object of providing activecompounds which have an activity comparable with olaflur, but containless by-products and are simpler to prepare.

The object set is achieved according to the invention by aminehydrofluorides of the general formula (I):

R—N(CH₂CH₂OH)₂.HF   (I)

where R is a straight-chain hydrocarbon residue having 10 to 20 carbonatoms.

It has namely been found that these amine hydrofluorides and mixtures oftwo or more thereof have an antibacterial activity which is very similarto that of theN′-octadecyl-N′,N,N-tris(2-hydroxyethyl)-1,3-propanediaminedihydrofluoride from the already-known olaflur. The antibacterial actionmanifests itself in the inhibition of the growth of a multiplicity ofmicro-organisms, for instance of Aspergillus niger, Candida albicans,Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus,Streptococcus faecalis and Enterobacter cloacae. The aminehydrofluorides according to the invention in particular inhibit thesugar degradation in acid-producing plaque bacteria and, owing to theformation of a hydrophobic film, increase the acid resistance of thehard tooth substance and thus have caries-prophylactic action. They alsofavour the remineralization of initial carious lesions.

The amine hydrofluorides according to the invention containstraight-chain (i.e. unbranched) hydrocarbon residues. They can havehydrocarbon residues with both an even- and odd-numbered chain length.Residues having an even-numbered chain length are preferred with regardto physiological acceptability. The residues can preferably be fullysaturated or mono-, di- or polyunsaturated. Examples of saturatedhydrocarbon residues having an even-numbered chain length are decyl,dodecyl (lauryl), tetradecyl (myristyl), hexadecyl (cetyl, palmityl),octadecyl (stearyl) and eicosanyl. Examples of unsaturated residueshaving an even-numbered chain length are 9-cis-octadecenyl (oleyl),9-trans-octadecenyl (elaidyl), cis,cis-9,12-octadecadienyl (linolyl),cis,cis,cis-9,12,15-octadecatrienyl (linolenyl) or 9-cis-eicosaenyl(gadolyl). Lauryl, myristyl, cetyl, oleyl and stearyl residues arepreferred.

The amine hydrofluorides are prepared according to the invention byreacting an amine of the general formula (II):

R—N(CH₂CH₂OH)₂   (II)

in which R is a hydrocarbon residue having 10 to 20 carbon atoms, withhydrogen fluoride. The reaction can be carried out in all solvents whichhave an adequate solubility for the free amine of the formula (II) andare not attacked by hydrogen fluoride. Examples of suitable solvents areC₁- to C₄-alcohols and dimethyl sulfoxide: ethanol is particularlypreferred. The addition of the hydrogen fluoride as an aqueous solution,i.e. as hydrofluoric acid , is preferred. The hydrogen fluoride ispreferably added in an amount from 1 to 5, particularly preferably from1.0 to 1.1, equivalents, based on the amine. The temperature of thereaction is not critical and can in general be between −10 and +100° C.,whereby the upper limit may be given by the boiling point of thesolvent, or the lower limit by the melting point of the solvent. Thepreferred temperature of the reaction is between 25° C. and 40° C. Afterthe completion of the addition of the hydrogen fluoride, the reactionmixture can be evaporated and dried, by means of which the aminehydrofluoride according to the invention is obtained. A possible smallhydrogen fluoride loss during the evaporation and drying can becompensated by subsequent addition of a corresponding amount ofhydrofluoric acid in the preparation of the formulations according tothe invention.

The amine of the formula (II) can be prepared in a manner which is knownor known per se by hydroxyethylation of a primary amine R—NH₂, in whichR has the above meaning, with ethylene oxide (oxirane), the ethoxylationtaking place virtually quantitatively only on the nitrogen atom.

The primary amine R—NH₂ can be obtained in a known manner from a fattyacid of the formula R—COOH, in which R has the above meaning, by meansof the synthesis steps amide formation/dehydration/catalytic reduction,as are also used in the synthesis of the already-known olaflur. Suitablefatty acids or fatty acid mixtures of the formula R—COOH and suitableamines or amine mixtures of the formula R—NH₂ are known and in somecases obtainable commercially.

According to a further variant, the amine of the formula (II) can beprepared by alkylation of diethanolamine in a nucleophilic S_(N)2substitution:

R—X+HN(CH₂CH₂OH)₂→R—N(CH₂CH₂OH)₂.HX

where R—X is the alkylating agent, R has the same meaning as in formula(II) and X is, for example, chlorine, bromine or iodine.

The amine of the formula (II) is first obtained here as an ammoniumsalt. This ammonium salt is deprotonated using a base, for exampleaqueous NaOH, and then reacted according to the invention with hydrogenfluoride.

The alkylating agent R—X can be obtained from a corresponding,commercially obtainable fatty alcohol by introducing a leaving group:

R—OH+HX→R—X+H₂O

where R—OH is the fatty alcohol, and HX is, for example, hydrogenchloride, hydrogen bromide or hydrogen iodide.

A separation of possible homologues and/or double bond isomers can becarried out at the stage of the fatty alcohol, e.g. by fractionaldistillation and/or recrystallisation, so that a pure fatty alcohol isobtained (for the necessary physical data cf., for example, Römpp,Chemielexikon [Chemical Encyclopedia], 9th Edition, Vol. 2, page 1337).

The amine hydrofluorides according to the invention are preferablyessentially free of di- or polyamine hydrofluorides, such as are typicalof the already-known olaflur. They are free, in particular if thepreparation route via the alkylation of highly pure diethanolamine isselected, of products in which the amino groups are over- orunder-hydroxyethylated (i.e. in that the amines are quaternary orsecondary after the hydroxyethylation) or the hydroxyethyl groups areetherified. The amine hydrofluorides according to the invention have adegree of hydroxyethylation of exactly two, if the route via thealkylation of diethanolamine is selected.

According to the invention, the object is also achieved by an aminehydrofluoride mixture comprising two or more compounds of the formula(I).

The mixtures of amine hydrofluorides according to the invention can bemixtures in any desired ratio of two or more amine hydrofluorides whichcan be prepared according to one of the above processes.

Mixtures of amine hydrofluorides are preferred which have been obtainedfrom a fatty acid mixture of an animal or vegetable fat or oil and whosehydrocarbon residues R therefore have a frequency distribution dependenton the chain length which reflects the frequency distribution of thecorresponding fatty acid homologues in this fatty acid mixture. Suchmixtures can be obtained by hydrofluoridation of mixtures of amines ofthe formula (II). The mixtures of amines are prepared here, startingfrom an animal or vegetable fat or oil, using the synthesis stepshydrolysis/amide formation/dehydration/catalyticreduction/hydroxy-ethylation in analogy to the corresponding synthesissteps for the already-known olaflur.

Examples of the vegetable oils or fats suitable for these mixtures ofamines of the formula (II) are almond oil, avocado pear oil, maize germoil, cottonseed oil, rapeseed oil, linseed oil, olive oil, peanut oil,pumpkin seed oil, rice bran oil, safflower oil, sesame oil, soya oil,sunflower oil, wheatgerm oil, babassu oil, coconut oil, palm kernel oil,rape oil and palm oil. Examples of animal fats or oils are bovinetallow, chicken fat, goat's fat, pork dripping, sheep tallow, variousfish oils and whale oil. A preferred animal fat is bovine tallow:preferred vegetable oils are soya oil, rape oil or soya oil/rape oilmixtures. A detailed table with the compositions of the fatty acidmixtures resulting from these animal or vegetable fats or oils is found,for example, in Ullmann's Encyclopaedia of Industrial Chemistry 5thEdition, Vol. A10, page 176 et seq. The amounts of saturated fatty acidscan be increased, if desired, by catalytic hydrogenation.

Mixtures of amines of the formula (II) which have been obtained from avegetable or animal fat or oil are obtainable commercially. Examples arethe products Ethomeen S/12 (obtained from the fatty acid mixture fromsoya oil), Ethomeen T/12 and Ethomeen HT/12 (both obtained from thefatty acid mixture from bovine tallow, the latter being hydrogenated)marketed by AKZO NOBEL. The main component in S/12 and T/12 isN-oleyldiethanolamine. The applicant was also able to order a mixture ofamines of the formula (II) , whose main component isN-stearyldiethanolamine, from WITCO. This mixture is obtained from thefatty acid mixture of bovine tallow, the oleyl residues beinghydrogenated to give stearyl residues.

A mixture of amine hydrofluorides according to the invention can also beobtained if a mixture of amine hydrofluorides which has been obtainedfrom the fatty acid mixture of a vegetable or animal fat or oil is mixedwith one or more pure amine hydrofluorides. Two or more mixtures ofamine hydrofluorides which have been obtained from different fats oroils in each case can also be mixed.

A fat such as is known in the art can also be reduced to a mixture offatty alcohols, and this fatty alcohol mixture can be processed, asdescribed above for the synthesis of amine hydrofluorides in pure formfrom pure fatty alcohols, to give a corresponding mixture of aminehydrofluorides.

The invention likewise relates to oral hygiene compositions comprisingat least one of the amine hydrofluorides according to the invention inan efficacious amount. They can be prepared in analogy to theconventional oral hygiene compositions and using the customaryauxiliaries and additives.

Preferably, the oral hygiene compositions according to the invention canalso contain a mixture of amine hydrofluorides obtained from a vegetableor animal oil or fat, in particular from bovine tallow, soya oil, rapeoil or soya oil/rape oil mixtures.

In addition to an amine hydrofluoride or a mixture of aminehydrofluorides, oral hygiene compositions according to the invention canalso preferably contain tin(II) fluoride. These tin fluoride-containingoral hygiene compositions are active against gingivitis, parodontitisand stomatitis, likewise being caries-prophylactically active due to thecontent of amine hydrofluorides. In such oral hygiene compositions, theamine hydrofluoride(s) according to the invention bring about apharmaceutical stabilization of the Sn(II) against precipitation to giveinsoluble tin(IV) oxide.

The lower limit for the content by weight of the amine hydrofluoride(s)in the oral hygiene composition is determined by the still-significantprophylactic action, i.e. in particular the antimicrobial orcaries-prophylactic action. The upper limit for the weight of the aminehydrofluoride(s) is not critical, it should, however, not be too highwith respect to possible toxic side effects.

In the case of an oral hygiene composition in the form of toothpastes,it is possible for amine hydrofluorides according to the inventionpreferably to be contained in amounts from 0.02 to 5% by weight,particularly preferably from 2 to 3% by weight.

The additives and auxiliaries for toothpastes according to the inventionare scouring agents, binding agents, plasticizers, moisturizing agentsand also flavourings and aromatic substances. Examples of scouringagents are alkaline earth metal phosphates (e.g. dicalcium phosphatedihydrate, dicalcium phosphate anhydride, tricalcium phosphate),insoluble alkali metal metaphosphates, finely ground or colloidalsilicas, aluminium hydroxide hydrates, aluminium silicates, aluminiummagnesium silicates and alkaline earth metal carbonates. Suitableplastics, e.g. polyethylene, can also be employed. These scouring agentsare customarily employed in amounts of 20 to 60% by weight. Bindingagents are gelling agents of natural or synthetic origin. Examples ofthese are water-insoluble alginates, carraghenates, guar gum,tragacanth, water-soluble cellulose ethers (e.g. methylcellulose,hydroxyalkylcelluloses, carboxymethylcellulose), water-soluble salts ofpolyacrylic acids (Carbopols), aerosils and bentonites. In general, thecontent of the binding agents is 0.5 to 10% by weight. Examples ofplasticizers and moisturizing agents are polyhydric alcohols such asglycerol, propylene glycol, sorbitol, mannitol, glucose syrup,polyethylene glycols, polypropylene glycols and polyvinylpyrrolidone.They are customarily employed in amounts from 10 to 40% by weight.Examples of flavourings are saccharin, quaternary ammoniumsaccharinates, cyclamates, coumarin and vanillin. Aromatic substancesare customarily ethereal oils, e.g. peppermint oil, spearmint oil,aniseed oil, menthol, anethole, citrus oil etc. or other essences suchas apple, eucalyptus or spearmint essence.

Rinsing solutions according to the invention are preferably aqueous,alcoholic or mixed aqueous/alcoholic solutions with one or more of theamine hydrofluorides according to the invention. It is possible for theamine hydrofluoride(s) according to the invention to be present inamounts from 0.02 to 2% by weight, preferably 0.2 to 0.3% by weight.Additives and auxiliaries for rinsing solutions, are, for example, theabovementioned flavourings and aromatic substances, but alsoemulsifiers, wetting agents, sorbitol, xylitol and various drugextracts.

As the carrier material, dental gels according to the invention containa swollen mixture of natural or synthetic hydrocolloids. Examples ofthese are methylcellulose, hydroxyalkylcelluloses,carboxymethylcellulose, water-soluble and swellable salts of thepolyacrylic acids, alginates, carraghenates and guar gum. Theabovementioned flavourings and aromatic substances and moisturizingagents and possibly also pigments can also be admixed in small amountsinto the respective gel base. It is possible for one or more of theamine hydrofluorides according to the invention to be contained inamounts from 0.02 to 10% by weight, preferably 4.9 to 5.0% by weight. Toconceal the taste and/or as an additional fluoride source, it is alsopossible to add sodium fluoride, in amounts up to 5% by weight.

Further examples of oral hygiene compositions according to the inventionare topical application solutions and chewable tablets. The content ofamine hydrofluorides in topical application solutions can alternativelybe higher than in rinsing solutions. In topical application solutions itcan typically be 5 to 25% by weight, preferably 15 to 25% by weight. Thesame substances can be used as additives in topical applicationsolutions as in the rinsing solutions. In the case of chewable tablets,amine hydrofluoride contents of typically 0.3 to 12% by weight,preferably 2 to 7% by weight, can be present. Additives for chewabletablets are binding agents and sucrose, glucose, lactose or preferablythe non-cariogenic sugar types such as xylitol, mannitol or sorbitol.They can be improved in flavour by addition of aromatic substances. Forthe production of chewable tablets according to the invention, processesand tabletting presses known from the conventional production ofchewable tablets can be employed.

In all oral hygiene compositions according to the invention, tin(II)fluoride can also be added in amounts of, as a rule, 0.001 to 2% byweight, as a solid or as, for example, an aqueous solution. The sameadditives and auxiliaries can be employed as in the tin fluoride-freeoral hygiene compositions. As solutions of tin(II) fluoride arestabilized by addition of the amine hydrofluorides according to theinvention, such solutions remain clear over a longer period and nocloudiness occurs. Combinations of the amine hydrofluorides according tothe invention and tin(II) fluoride are therefore particularly suitablefor use in oral hygiene compositions in the form of rinsing solutions.Rinsing solutions which contain efficacious amounts of one or more aminehydrofluorides and tin(II) fluoride are a preferred embodiment of theoral hygiene compositions according to the invention.

The present invention is now illustrated further by the followingexamples. All quantitative data in per cent, ppm and parts relate, ifnot mentioned otherwise, to weights.

EXAMPLE 1 Preparation of Amine Hydrofluorides

A weighed amount of a mixture of amines of the formula (II) (EthomeenT/12 from AKZO NOBEL, typical distribution of the chain length of R: 1%C₁₂, 4% C₁₄, 31% C₁₆, 64% C₁₈) was placed into a suitable reactionvessel having a stirrer, homogenizer, temperature control withtemperature indicator, vacuum equipment and an HF-resistant meteringdevice, this amount being selected such that the filling of the vesselwas at most 10 to 20% by volume. The mixture was dissolved in two partsof ethanol at room temperature. 1.015 equivalents of hydrogen fluoridewere added from the metering device in the form of 40% strength aqueoushydrofluoric acid. Care was taken here that the temperature of themixture did not exceed 40° C. The metering device was then rinsed outwith the same volume of distilled water. The mixture was evaporated todryness by careful evacuation (foam formation) and a maximum mixturetemperature of 65° C.

The mixture of amine hydrofluorides prepared here is designated in thefollowing as “oleyl amine fluoride”.

EXAMPLE 2 Preparation of Amine Hydrofluorides

The procedure was as in Example 1, except that the starting mixture wasanother mixture of amines of the formula (II) (Ethomeen HT/12 from AKZONOBEL, typical distribution of the chain length of R: 1% C₁₂, 4% C₁₄,31% C₁₆, 64% C₁₈; essentially saturated by hydrogenation) instead ofEthomeen T/12.

For the mixture of amine hydrofluorides prepared here, the term “stearylamine fluoride” is used in the following.

EXAMPLE 3 Toothpaste

The reaction container used was a mixer with a homogenizer. 62 g ofstearyl amine fluoride from Example 2 (corresponding to 2.48% of thefinished toothpaste) were added to the mixer and dissolved in 1.097 kgof water at 55° C. 600 g of 70% sorbitol, 37.5 g of peppermint essence,625 g of silica gel, 50 g of hydroxyethylcellulose (Tylose H 10,000 P,Hoechst), 25 g of titanium dioxide and 3.75 g of saccharin were thenadded. The mixture was stirred at 100 rpm and level 1 of the homogenizerfor 50 minutes at 35° C. and a pressure of 0.5 bar, then for a further15 minutes at room temperature and a pressure of 0.1 bar.

EXAMPLE 4 Toothpaste

The reaction container used was a mixer having a homogenizer. 61.63 g ofoleyl amine fluoride from Example 1 (corresponding to 2.465% of thefinished toothpaste) were added to the mixer and dissolved in 0.5 kg ofwater at room temperature. 1.22 g of 42.21% strength hydrofluoric acid,600 g of 70% sorbitol, 37.5 g of peppermint essence, 596 g of water, 625g of silica gel, 50 g of hydroxyethylcellulose (Tylose H 10,000 P,Hoechst), 25 g of titanium dioxide and 3.75 g of saccharin were thenadded. The mixture, was stirred at 100 rpm and level 1 of thehomogenizer for 60 minutes at 35° C. and a pressure of 0.5 bar, then fora further 15 minutes at room temperature and a pressure of 0.1 bar.

EXAMPLE 5 Toothpaste

The reaction container used was a mixer with a homogenizer. 69.5 g ofstearyl amine fluoride from Example 2 (corresponding to 2.78% of thefinished toothpaste) were added to the mixer and dissolved in 1.014 kgof water at 55° C. 750 g of 70% sorbitol, 30 g of eucalyptus essence,325 g of polyethylene, 175 g of silica gel, 10 g of saccharin, 47.5 g ofhydroxyethylcellulose (Tylose H 10,000 P, Hoechst), 25 g of titaniumdioxide and a solution of 3.75 g of NaOH in 50 g of water were thenadded. The mixture was stirred at 100 rpm and level 1 of the homogenizerfor 60 minutes at 32° C. and a pressure of 0.6 bar, then for a further15 minutes at room temperature and a pressure of 0.1 bar.

EXAMPLE 6 Toothpaste

The reaction container used was a mixer with a homogenizer. 69.0 g ofoleyl amine fluoride from Example 1 (corresponding to 2.761% of thefinished toothpaste) were added to the mixer and dissolved in 0.5 kg ofwater at room temperature. 1.36 g of 42.21% strength hydrofluoric acid,750 g of 70% sorbitol, 30 g of eucalyptus essence, 513 g of water, 325 gof polyethylene, 175 g of silica gel, 10 g of saccharin, 47.5 g ofhydroxyethylcellulose (Tylose H 10,000 P, Hoechst) and 25 g of titaniumdioxide and a solution of 3.75 g of NaOH and 50 g of water were thenadded. The mixture was stirred at 100 rpm at level 1 of the homogenizerfor 65 minutes at 38° C. and a pressure of 0.6 bar, then for a further15 minutes at 25° C. and a pressure of 0.1 bar.

EXAMPLE 7 Rinsing Solution

The preparation was carried out under nitrogen protective gas. 2.48 g ofstearyl amine fluoride from Example 2, (corresponding to 0.248% of thefinished rinsing solution) were dissolved in 918 g of water at 50° C. ina reaction vessel. 2 g of PEG-40-hydrogenated castor oil (Cremophor RH410, BASF), 50 g of ethanol, 1 g of peppermint/spearmint essence, 25 gof xylitol, 250 mg of Acesulfam K, 0.5 g of 0.4% strength pigmentsolution of Ariavit Blue 3.85 CI 42051 were then added and dissolved.

EXAMPLE 8 Rinsing Solution

0.575 g of tin(II) fluoride were additionally added to a rinsingsolution prepared according to the recipe of Example 7 and dissolved.

EXAMPLE 9 Rinsing Solution

The preparation was carried out under nitrogen protective gas. 25 g ofxylitol and 0.5 g of 0.4% strength pigment solution of Ariavit Blue 3.85CI 42051 were dissolved in 918 g of water in a reaction vessel. 2.47 gof oleyl amine fluoride from Example 1 (corresponding to 0.247% of thefinished rinsing solution), 2 g of PEG-40-hydrogenated castor oil(Cremophor RH 410, BASF), 50 g of ethanol, 1 g of peppermint/spearmintessence, 250 mg of Acesulfam K and 0.048 g of 42.2% strengthhydrofluoric acid were then added and dissolved.

EXAMPLE 10 Rinsing Solution

0.556 g of tin(II) fluoride were additionally added to a rinsingsolution prepared according to the recipe of Example 9 and dissolved.

EXAMPLE 11 Dental Gel

The reaction container used was a mixer with a homogenizer. 124 g ofstearylamine fluoride from Example 2(corresponding to 4.96% of thefinished dental gel) were added to the mixer and dissolved in 1.969 kgof water at 90° C. 45 g of peppermint/apple essence, 55.5 g of sodiumfluoride, 10 g of saccharin, 250 g of propylene glycol and 46 g ofhydroxyethylcellulose (Tylose H 10,000 P, Hoechst) were then added. Themixture was stirred at 100 rpm and level 1 of the homogenizer for 40minutes at 30° C. and a pressure of 0.4 bar, then for a further 25minutes at room temperature and a pressure 0.1 of bar.

EXAMPLE 12 Dental Gel

The reaction container used was a mixer with a homogenizer. 123 g ofoleylamine fluoride from Example 1 (corresponding to 4.93% of thefinished dental gel) were added to the mixer and dissolved in 1,000 kgof water. 2.4 g of 42.21% strength hydrofluoric acid, 45 g ofpeppermint/apple essence, 55.5 g of sodium fluoride, 10 g of saccharin,250 g of propylene glycol and 46 g of hydroxyethylcellulose (Tylose H10,000 P, Hoechst) were then added. Dilution was carried out with afurther 968 g of water. The mixture was stirred at 100 rpm and level 1of the homogenizer for 50 minutes at 30° C. and a pressure of 0.4 bar,then for a further 75 minutes at 25° C. and a pressure of 0.1 bar.

EXAMPLE 13 Chewable Tablet

15 parts of oleylamine fluoride were suspended in about 20 parts ofwater and subsequently granulated by spray drying (active compoundgranules). A mixture of 0.6 parts of saccharin, 3 parts of Plasdone(cross-linked polyvinylpyrrolidone), 7.5 parts of Avicel (nativecellulose), 5 parts of talc, 48 parts of rice starch, 0.9 parts ofpeppermint oil and 220 parts of sorbitol were also granulated by spraydrying (auxiliary granules). The active compound granules were mixedwith the auxiliary granules in a gravity mixer and tableted to give abatch of chewable tablets in a commercially available eccentric press.The average weight per tablet was 300 mg.

EXAMPLE 14 Topical Application Solution

19.85 parts of oleyl amine fluoride, corresponding to 19.85% of thefinished topical application solutions, 0.15 parts of saccharin, 2.5parts of essence mixture (consisting for its part of 30 parts of aniseedoil, 7.5 parts of menthol, 1.0 parts of vanillin, 6.0 parts of spearmintoil and 55.5 parts of peppermint oil) and 77.5 parts of water weremixed. A ready-to-use topical application solution was obtained.

EXAMPLE 15 Measurement of the Total Fluoride Content of AmineHydrofluoride Mixtures

A weighed amount of oleyl amine fluoride from Example 1 was dissolved inwater and the fluoride content was determined by alkalimetric titrationwith 0.1N aqueous tetrabutylammonium hydroxide solution (assumption ofequimolar amounts of fluoride and ammonium groups). Measurements showeda fluoride content of 4.28%. Analogously, a fluoride content of 5.04%was found for the stearyl amine fluoride of Example 2.

EXAMPLE 16 Measurement of the Total Fluoride Content of Toothpastes andDental Gels

Measurement was carried out using a fluoride electrode and a measuringapparatus 610 from METROHM. The calibration of the electrode was carriedout with a calibration solution of 45.24 ppm of fluoride, which was madeup as follows:

a) 20 ml of fluoride standard solution in water (containing 200 mg ofNaF/litre of solution),

b) 20 ml of TISAB buffer solution, pH 5.0 to 5.5.

The TISAB buffer was prepared here as follows:

Solution I: 5 g of Komplexon IV, 57 g of glacial acetic acid and 58 g ofsodium chloride in 500 g of water;

Solution II: 32 g of NaOH in 350 g of water.

Solutions I and II were mixed and diluted to 1,000 ml with water.

The measuring solution of the sample was prepared by adjusting anaccurately weighed amount of sample of approximately 1 g to 20 g withwater and mixing with 20 g of TISAB buffer. The measuring solution wasmeasured under the same conditions as the calibration solution. Thecalculation of the fluoride content of the sample was carried out bymeans of the general formula: $\begin{matrix}{{{ppm}\quad F^{-}} = {45.24 \times \frac{{sample}\quad {solution}\quad {measurement}}{{calibration}\quad {solution}\quad {measurement}} \times}} \\{= \frac{40\quad g}{{weight}\quad {of}\quad {sample}\quad g}}\end{matrix}$

The total contents shown in Table 1 were found.

TABLE 1 Toothpaste from Example 3 1243 ppm of F⁻ Toothpaste from Example4 1170 ppm of F⁻ Toothpaste from Example 5 1432 ppm of F⁻ Toothpastefrom Example 6 1390 ppm of F⁻ Dental gel from Example 11 1.25% F⁻ Dentalgel from Example 12 1.32% F⁻

EXAMPLE 17 Measurement of the Total Fluoride Content of RinsingSolutions

Measurement was carried out using a fluoride electrode and a measuringapparatus 610 from METROHM. The calibration of the electrode was carriedout with a calibration solution of 125 ppm of fluoride, which was madeup as follows:

a) 20 ml of fluoride standard solution (250 ppm of fluoride) influoride-free rinsing solution,

b) 20 ml of TISAB buffer (cf. Example 16).

The measuring solution of the sample was prepared by mixing 20 ml ofrinsing solution sample and 20 ml of TISAB buffer. The measuringsolution was measured under the same conditions as the calibrationsolution. The calculation of the fluoride content of the sample wascarried out by means of the general formula:${{ppm}\quad F^{-}} = {250\quad \times \frac{{sample}\quad {solution}\quad {measurement}}{{calibration}\quad {solution}\quad {measurement}}}$

The total contents shown in Table 2 were found.

TABLE 2 from Example 9 250 ppm of F⁻ from Example 10 250 ppm of F⁻

EXAMPLE 18 Determination of the Microbiological Activity of AmineHydrofluorides against Staphylococcus aureus (ATCC 6538) andStreptococcus faecalis (ATCC 10541) in the Test for the Determination ofthe Minimum Inhibitory Concentration (MIC Test)

These two micro-organisms were selected because they are of importanceas cocci representative of oral cavity cocci. Three stock solutions ofone part by weight each of a bacteria-containing medium consisting of aso-called shaker culture based on Caso broth, adjusted to 100,000bacterial cells/μl, and one part by weight each of three physiologicalsaline solutions which contained oleyl amine fluoride from Example 1.(for stock solution A) or stearyl amine fluoride from Example 2 (forstock solution B) or already-known olaflur (for stock solution C) wereprepared. The concentration of the amine hydrofluorides in thephysiological saline solutions was such that a fluoride concentration of3,000 ppm of F⁻/100 g of stock solution resulted in each finished stocksolution. A geometric dilution series was formed from each stock mixtureby diluting with physiological saline solution (dilution factor 2 ineach case). It was investigated at which dilutions a significantinhibition of the micro-organisms was no longer observed. Table 3 showsthe highest dilution stages compared with the stock mixtures at whichthe bacteria were still destroyed in an actual experiment.

TABLE 3 compared with compared with compared with stock mixture A stockmixture B stock mixture C Staph. aureus 1:8192 1:2048 1:4096 Str.faecalis 1:8192 1:2048 1:8192

Taking into account the biological variability in the vitality of thebacteria, the three active substances are to be regarded asapproximately equally active.

EXAMPLE 19 Determination of the Microbiological activity of toothpasteformulations against Staphylococcus aureus (ATCC 6538) and Streptococcusfaecalis (ATCC.10541) in the MIC Test

Three stock mixtures of one part by weight each of a bacteria-containingmedium consisting of a shaker culture based on Caso broth, adjusted to100,000 bacterial cells/μl and one part by weight of a toothpaste (stockmixture A: toothpaste from Example 3; stock mixture B: toothpaste fromExample 4; stock mixture C: commercial toothpaste containing knownolaflur) were prepared. The fluoride content by weight was equal in allthe stock mixtures. A geometric dilution series of each stock mixturewas formed by diluting with physiological saline solution (dilutionfactor 2 in each case). It was investigated at which dilutions asignificant inhibition of the micro-organisms was no longer observed.Table 4 shows the highest dilution stages compared with the stockmixtures in which the bacteria were still destroyed in an actualexperiment.

TABLE 4 compared with compared with compared with stock mixture A stockmixture B stock mixture C Staph. aureus 1:512 1:4096 1:4096 Str.faecalis 1:256 1:4096 1:1024

Taking into account the biological variability in the vitality of themicro-organisms, the two toothpastes based on oleyl amine fluoride orolaflur exhibit comparable efficacy.

What is claimed is:
 1. Amine hydrofluoride of the general formula (I):R—N(CH₂CH₂OH)₂.HF   (I) in which R is a straight-chain hydrocarbonresidue having 10 to 20 carbon atoms.
 2. Amine hydrofluoride accordingto claim 1, wherein the hydrocarbon residue R has an even number ofcarbon atoms.
 3. Amine hydrofluoride according to claim 1, wherein thehydrocarbon residue R is a lauryl, myristyl, cetyl, oleyl, linolyl,linolenyl, stearyl, eicosanyl or eicosaenyl residue.
 4. Anantibacterially active agent of the general formula (I):R—N(CH₂CH₂OH)₂.HF   (I) in which R is a straight-chain hydrocarbonresidue having 10 to 20 carbon atoms.
 5. Amine hydrofluoride mixturecomprising two or more compounds of the general formula (I):R—N(CH₂CH₂OH)₂.HF   (I) in which R is a straight-chain hydrocarbonresidue having 10 to 20 carbon atoms.
 6. Mixture according to claim 5,obtained from the fatty acid mixture of a vegetable or animal fat oroil.
 7. Mixture according to claim 5 or 6, obtained from bovine tallow,soya oil, rapeseed oil or a soya oilrapeseed oil mixture.
 8. Process forthe preparation of an amine hydrofluoride of the general formula (I):R—N (CH₂CH₂OH)₂.HF   (I) in which R is a straight-chain hydrocarbonresidue having 10 to 20 carbons atoms, comprising reacting an amine ofthe general formula (II): R—N (CH₂CH₂OH)₂   (II) in which R is astraight-chain hydrocarbon residue having 10 to 20 atoms, with hydrogenfluoride.
 9. Oral hygiene composition, comprising at least one aminehydrofluoride of the general formula: R—N(CH₂CH₂OH)₂.HF   (I) in which Ris a straight-chain hydrocarbon residue having 10 to 20 carbon atoms, inan antimicrobially or caries-prophylactically efficacious amount, and acustomary additive or auxiliary suitable for use in oral hygienecompositions.
 10. Oral hygiene composition according to claim 9,comprising a mixture of amine hydrofluorides of the formula (I) obtainedfrom bovine tallow, soya oil, rapeseed oil or a soya oil/rapeseed oilmixture.
 11. Oral hygiene composition according to claim 9, in the formof a toothpaste and comprising one or more amine hydrofluorides of theformula (I) in an amount from 0.02 to 5, per cent by weight.
 12. Oralhygiene composition according to claim 9, in the form of a rinsingsolution and comprising one or more amine hydrofluorides of the formula(I) in an amount from 0.02 to 2, per cent by weight.
 13. Oral hygienecomposition according to claim 9, in the form of a dental gel andcomprising one or more amine hydrofluorides of the formula (I) in anamount from 0.02 to 10, per cent by weight.
 14. Oral hygiene compositionaccording to claim 9 in the form of a topical application solution andcomprising one or more amine hydrofluorides of the formula (I) in anamount from 5 to 25, per cent by weight.
 15. Oral hygiene compositionaccording to claim 9 in the form of a chewable tablet and comprising oneor more amine hydrofluorides of the formula (I) in an amount from 0.3 to12, per cent by weight.
 16. Oral hygiene composition according to claim9, further including tin (II) fluoride in an amount of up to 2% byweight.
 17. A method of preparation of an oral hygiene composition,comprising admixing am amine hydrofluoride of the general formula (I):R—N(CH₂CH₂OH)₂.HF   (I) in which R is a straight-chain hydrocarbonresidue having 10 to 20 carbon atoms and a customary auxiliary oradditive suitable for use in oral hygiene compositions.
 18. A method ofcaries-prophylactic treatment of a tooth enamel, comprising applying anamine hydrofluoride of the general formula (I): R—N(CH₂CH₂OH)₂.HF   (I)in which R is a straight-chain hydrocarbon residue having 10 to 20carbons atoms, to said tooth enamel.
 19. A method of treatment ofgingivitis, periodontitis or stomatitis comprising orally administeringan amine hydrofluoride of the general formula (I): R—N(CH₂CH₂OH)₂.HF  (I), in which R is a straight-chain hydrocarbon residue having 10 to20 carbon atoms, and tin (II) fluoride.